Cpg Island Methylator Phenotype With Distinctly Different Prognosis And Molecular Features In Pancreatic Cancer Patient

Abstract BackgroundCpG island methylator phenotype (CIMP), featured with concurrent and widespread hypermethylation of a cluster of CpGs, has been reported to play an important role in carcinogenesis. Limited studies have investigated the CIMP in pancreatic cancer (PC). The aim of this study was to explore the CIMP in PC patients and its clinical-pathological and genomic characteristics. Methods:DNA methylation, somatic mutation, mRNA and corresponding clinical data of PC patients were downloaded from TCGA (184 patients) and ICGC (264 patients). Univariate and multivariate regression analysis were used to identify prognosis related CpGs. Consensus clustering analysis was used for identification of the CIMP in PC patients. ESTIMATE and CIBORORT were used for estimation of tumor microenvironment (TME) in PC patients.ResultsIn TCGA PC cohort, 22,450 differential CpGs, including 12,937 hypermethylated CpGs and 9,513 hypomethylated CpGs were identified between185 PC patients and 10 normal controls. Univariate and multivariate Cox analysis further screened out 72 OS related CpGs and three distinct CIMP groups with distinctly different prognosis and molecular features, including CIMP-L subgroup, CIMP-M subgroup and CIMP-H subgroup were identified based on unsupervised consensus clustering analysis of these CpGs. Patients of the CIMP-H subgroup had poorer OS and RFS, while patients of CIMP-L subgroup had better OS and RFS. The CIMP status were also an independent prognostic factors for OS and PFS. In molecular features, significantly higher somatic mutation burdens and tumor mutational burden were found at patients of CIMP-H subgroup compared to that in patients of CIMP-L subgroup. Besides, lower stromal score, immune score and higher cancer stemness indices and tumor purity were also found at patients of CIMP-H subgroup compared to that in patients of CIMP-L subgroup. Correspondingly, significantly total T cells, total B cells, CD8 T cells, memory CD4 T cells and higher regulatory T cells were found at patients of CIMP-H subgroup. Moreover, significantly lower expression of immune checkpoint genes, such as PD-1, CTLA4, CD86, VTCN1 and LAG-3 were also found at patients of CIMP-H subgroup compared to that in patients of CIMP-L subgroup. In the end, we validated the CIMP status in PC patients of ICGC dataset.ConclusionThree distinct CIMP subgroups of PC patients with distinct clinical characteristic, prognosis, gene mutation landscape and TME were identified and validated. The CIMP may help to make an assertion to provide specific and efficient treatment options for patients of different subtypes.